DE1620189B1 - 4- (2'-Carbo-alpha-glyceryloxy-phenylamino) -chloroquinoline-acetonide and a process for their preparation - Google Patents

Description

The invention relates to new 4- (2'-carbo-a-glyceryloxy-phenylarnino) -chloroquinoline-acetonide of the general formula

NH

COO - CH ₂ - CH - CH ₂

in which a substituent X is a chlorine atom and the others represent a hydrogen atom and a method for their production.

These new quinoline derivatives have anti-inflammatory activity and remarkable analgesic activity. In terms of their anti-inflammatory activity and toxicity, they were compared with the well-known 4- (2 ^/ -Carbo-a-glyceryloxy-phenylamino) -7-chloroquinoline.

Anti-inflammatory activity

The method used is described in French patent specification 2413 M and consists in causing inflammatory edema by injecting 500 γ naphthoylheparamine under plantar fascia in the hind paws of rats. The products to be tested were administered buccally 1 hour before the injection. The ED _{50 of} the substances to be examined was determined, ie the dose which causes a 50% reduction in udema.

The following results were obtained:

7-chlorine derivative: ED ₅₀ = 33 mg / kg,
8-chlorine derivative: ED ₅₀ ~ 55 mg / kg,

4- (2'-Carbo-a-glyceryloxy-phenylamino) -7-chloroquinoline: ED ₅₀ = 60 mg / kg.

NH-

COOR

II

45

Acute toxicity in the mouse (buccal route)

7-chlorine derivative: DLs ₀ = 3 g / kg,
8-chlorine derivative: DL ₅₀ = 3.5 g / kg,

4- (2'-Carbo-a-glyceryloxy-phenylamino) -7-chloroquinoline: DL ₅₀ == a little above 2 g / kg.

The new acetonides are prepared by using a 4- (2'-CaIbalkoxy-phenylamino ^ chloroquinoline in a manner known per se the general formula

55

in which R is a lower alkyl radical, in the presence of an alkali metal or an amide one Reacts alkali metal with glycerol acetonide

The following examples illustrate the invention.

example 1

4- (2'-Carbo-a-glyceryloxy-phenylamino) -8-c-Morquinoline-acetonide

43 ecm of glycerol acetonide are added at 30 ecm anhydrous toluene, heated under a nitrogen atmosphere at a temperature of 120 to 125 ° C, The water-toluene azeotrope distills off and draws finally the toluene in vacuo.

After cooling to a temperature of 70 ° C 130 mg of sodium amide are introduced, and the mixture is heated IV ₂ hours to about 90 ⁰ C,

Thereafter, the temperature is brought to 6O ⁰ C, then 10.4 g of 4- (2'-carbomethoxy-phenylamino) -8-chlorchinoUn be introduced, and it is in the: heated for 5 hours at about 80 ° C vacuum.

It is cooled, the solution is poured into an internal mixture of water and methylene chloride (10: 1) stirred and decanted.

The aqueous phase is extracted with methylene chloride, the combined methylene chloride extracts are washed with water, dried and distilled to dryness.

The residue is triturated with petroleum ether, filtered off and dried. So 12.5 g of the 4 - (2 '- Carbo - α - glyceryloxy - phenylamino) - 8 - chloroquinoline acetonides obtained, which melts at 115 ° C after recrystallization from ethanol.

The product is insoluble in water and ether; it is in acetone, benzene, chloroform and in the heat soluble in ethanol and isopropyl ether.

Analysis: C ₂₂ H ₂ IO ₄ N ₂ Cl = 412.86.

Calculated ... C63.99, H5.13, N6.78, Cl8.59%; found .... C 64.1, H 5.1, N 7.1, Cl 8.6%,

The 4- (2'-carbomethoxyphenylanrino) -8-chloroquinoline required as starting material is prepared in the following way: 15 g of 4,8-dichloroquinoline, prepared according to D. S. Tarbe 11 (Journ, Am. Chem. Soc., 68, p. 1277 [1946]), in 75 ecm 2N hydrochloric acid introduced, 11.5 g of anthranilic acid methyl ester are then added. The whole will heated under reflux with stirring for 3 hours.

It is then cooled to ice bath temperature for 1 hour and the precipitated chlorohydrate des 4 - (2 '- Carbomethoxyphenylamino) - 8 - chloroquinolines filtered off with suction and washed with water.

To obtain the free base, the hydrochloride is dissolved in 200 ecm of ethanol, 50 ecm more concentrated Ammonia are then added until the reaction is clearly alkaline, and the whole thing is brought to ice bath temperature chilled. The precipitate formed is filtered off with suction, washed with ether and dried. To

recrystallization from ethanol gives 13 g of 4 - (2 '- carbomethoxy - phenylamino) - 8 - chloroquinoline obtained from melting point 183 to 184 ° C.

Example 2

4- (2'-Carbo-a-gryceryloxy-phenylamino) -7-chloroquinoline-acetonide

IO

To 1000 ecm of anhydrous glycerol acetonide which has been heated to 70 to 75 ° C., 5 g of sodium amide are added with stirring and while flushing with nitrogen, and IV is heated to about 90 to 95 ° C. for _{2 hours.} The solution is then cooled to about 60 ° C., 500 g of 4 - (2 '- carbomethoxyphenylamino) - 7 - chloroquinoline, which was prepared according to the process described in German patent 1 205 100, are then slowly introduced with stirring.

Then the reaction mixture is gradually heated up to a temperature of 80 ° C and 5 hours kept at this temperature.

The reaction mixture is then cooled to room temperature and poured into a mixture of Poured methylene chloride and water (1:14). It is stirred for 15 minutes; then the organic Phase decanted.

After renewed extraction of the aqueous phase with methylene chloride, the organic phases become combined, filtered, washed with water and distilled to dryness.

The residue is triturated with petroleum ether, filtered off and dried. The 4- (2'-Carbo-a-glyceryloxyphenylamino) -7-chloroquinoline-aceto- nid melts after recrystallization from ethanol at 108 ° C; Yield 615 g; 94% of theory,

Claims (4)

Patent claims: 1. 4- (2'-Carbo-a-glyceryloxy-phenylamino) -chloroquinoline-acetonide the general formula NH COO - CH ₂ - CH - CH CH, wherein one substituent X is a chlorine atom and the other is a hydrogen atom. 2. 4 - (2 '- Carbo - α - glyceryloxy - phenylamino) -8-chloroquinoline acetonide. 3.4- (2 '- Carbo - α - glyceryloxy - phenylamino) -7-chloroquinoline acetonide. 4. Process for the preparation of the compounds according to claim 1, characterized in that a 4- (2'-carbalkoxyphenylamino) chloroquinoline of the general type is used in a manner known per se formula NH- COOR in which R is a lower alkyl radical, in the presence of an alkali metal or an amide of an alkali metal with glycerol acetonide.